Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States.
Departments of Chemistry and Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
Eur J Med Chem. 2023 Dec 15;262. doi: 10.1016/j.ejmech.2023.115876. Epub 2023 Oct 16.
The EphA4 receptor tyrosine kinase plays a role in neurodegenerative diseases, inhibition of nerve regeneration, cancer progression and other diseases. Therefore, EphA4 inhibition has potential therapeutic value. Selective EphA4 kinase inhibitors are not available, but we identified peptide antagonists that inhibit ephrin ligand binding to EphA4 with high specificity. One of these peptides is the cyclic (βAPYCVYRβASWSC-NH), which inhibits ephrin-A5 ligand binding to EphA4 with low nanomolar binding affinity and is highly protease resistant. Here we describe modifications of that yield two different key derivatives with greatly increased half-lives in the mouse circulation, the lipidated and the PEGylated . These two derivatives inhibit ligand induced EphA4 activation in cells with sub-micromolar potency. Since they retain high potency and specificity for EphA4, lipidated and PEGylated derivatives represent new tools for discriminating EphA4 activities and for preclinical testing of EphA4 inhibition in animal disease models.
EphA4 受体酪氨酸激酶在神经退行性疾病、神经再生抑制、癌症进展和其他疾病中发挥作用。因此，EphA4 抑制具有潜在的治疗价值。虽然目前还没有选择性 EphA4 激酶抑制剂，但我们已经鉴定出了一些肽类拮抗剂，它们能以高特异性抑制 EphA4 与 ephrin 配体的结合。其中一种肽是环状的 (βAPYCVYRβASWSC-NH)，它能以低纳摩尔亲和力抑制 EphA4 与 ephrin-A5 配体的结合，并且具有高度的抗蛋白酶能力。本文中，我们描述了对 进行修饰，得到了两种不同的关键衍生物，它们在小鼠循环中的半衰期大大延长，分别是脂质化的 和聚乙二醇化的 。这两种衍生物以亚微米摩尔的效力抑制配体诱导的 EphA4 激活。由于它们对 EphA4 仍保持高效力和特异性，脂质化和聚乙二醇化的 衍生物代表了区分 EphA4 活性的新工具，也代表了 EphA4 抑制在动物疾病模型中进行临床前测试的新工具。
